WO1995024478A1 - Proteines synthetiques utilisables en implants - Google Patents

Proteines synthetiques utilisables en implants Download PDF

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Publication number
WO1995024478A1
WO1995024478A1 PCT/US1995/002772 US9502772W WO9524478A1 WO 1995024478 A1 WO1995024478 A1 WO 1995024478A1 US 9502772 W US9502772 W US 9502772W WO 9524478 A1 WO9524478 A1 WO 9524478A1
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Prior art keywords
gly
gly val
val pro
gly ala
ala
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PCT/US1995/002772
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English (en)
Inventor
Joseph Cappello
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Protein Polymer Technologies, Inc.
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Application filed by Protein Polymer Technologies, Inc. filed Critical Protein Polymer Technologies, Inc.
Priority to JP52357195A priority Critical patent/JP3378254B2/ja
Priority to EP95913976A priority patent/EP0804595B1/fr
Priority to DE69535895T priority patent/DE69535895D1/de
Publication of WO1995024478A1 publication Critical patent/WO1995024478A1/fr

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    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F4/00—Monocomponent artificial filaments or the like of proteins; Manufacture thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/18—Manufacture of films or sheets
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/61—Fusion polypeptide containing an enzyme fusion for detection (lacZ, luciferase)
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00—Characterised by the use of proteins; Derivatives thereof

Definitions

  • the field of this invention is the production and use of bioresorbable polypeptide polymers.
  • Such products should have the desired mechanical properties of tensile strength, elasticity, formability, and the like, provide for controlled resorption, and be physiologically acceptable.
  • Protein copolymers are provided having segments varying in the number of repetitive units, based on fibroin and elastin.
  • the protein copolymers and silk homopolymers find use in the production of a wide variety of implantable devices and components thereof.
  • Implantable devices and components thereof comprised of recombinant novel copolymers having alternating segments of repetitive units based on fibroin (silk) in combination with elastin or recombinant polymers of fibroin.
  • the units for the most part are GAGAGS (SEQ ID NO:01) and VPGVG (SEQ ID NO:02) , respectively, although some variations are permitted, such as the particular order of the amino acids in the sequence and conservative substitutions, such as, but not limited to, replacing serine with threonine and glycine with alanine.
  • the copolymers by varying the ratio of the two different units, the length of the segments comprising each of the units, the molecular weight, any intervening sequences, modifications to the individual repeating units, and the like, one can vary the tensile properties of the product only moderately, such as elasticity, stiffness, hardness, ease of processing, and flexibility, while one can substantially vary the rate of resorption. Faster resorption can be achieved by . reducing the number of repeating units of silk in the silk segment below about 8 units or increasing the number of elastin units per elastin segment to greater than 8, individually or in combination.
  • the ratio of the average number of elastin units to the average number of silk units per segment of the repetitive units will be in the range of about 0.5, usually about 1-5.
  • For the elastin units there will usually be at least two, more usually at least about four, generally ranging from about 6-32, more usually from about 6-18, preferably from about 6-16.
  • the percent of amino acids contributed by the silk units will generally range from about 15-65%, more usually from about 15-60%, preferably about 20-55%.
  • copolymers which find use in the invention will generally range from about 15-80% of amino acids provided by fibroin units, where the average number of elastin to silk units will range from about 0 to 8.
  • the polymers will be at least about 15 kDa and generally not more than about 150 kDa, usually not more than about 125 kDa, preferably ranging from about 35-100 kDa.
  • the number of segments will provide for the desired molecular weight. Therefore, the number of segments can vary widely, depending upon the size of each individual segment. Thus, the number of segments may vary from about 2-40, more usually ranging from about 6-20. Based on the method of preparation, there may be non-repetitive units at the N- and C- termini.
  • the terminal sequences will contribute fewer than ten number percent of the amino acids, more usually fewer than five number percent of the amino acids. Generally, the sequence will range from about 0-125 amino acids, more usually from about 0-60 amino acids, where the total number of amino acids will generally not exceed about 100 amino acids, more usually not exceed about 50 amino acids.
  • the polymers may be modified by introducing intervening sequences between segments or blocks of segments, where the total number of repeating units per block may vary from about 4 to 40, thus involving two or more segments.
  • the intervening sequences may include from about 1 to 60, usually about 3 to 40 amino acids, and may provide for a wide variety of properties.
  • amino acids which have chemically reactive sidechains one may provide for sites for linking a variety of chemically or physiologically active compounds, for cross-linking, for covalently bonding compound which may change the rate of resorption, tensile properties or the like.
  • amino acids such as cysteine, aspartic acid, glutamic acid, lysine and arginine may be incorporated in these intervening sequences.
  • sequence may provide for sequences which have physiological activity, such as cell binding, specific protein binding, enzyme substrates, specific receptor binding, and the like.
  • physiological activity such as cell binding, specific protein binding, enzyme substrates, specific receptor binding, and the like.
  • the polymers have good mechanical properties to form a wide variety of products.
  • the protein polymers may be drawn, molded, cast, spun, extruded, or the like, in accordance with known ways for forming structures such as films, formed objects, fibers, or unformed structures, such as amorphous masses, and the like.
  • gels may be formed which may be shaped in a variety of ways, depending upon the particular application.
  • the compositions can be sterilized by conventional ways to provide sterile products.
  • compositions can be used to provide a wide variety of devices, such as membranes, sutures, staples, bone pins, screws, wound dressings, and as drug depots, where the products may be formed prior to implantation or in situ .
  • the compositions as formed are found to provide the necessary mechanical properties for the particular applications, the resorption times can be controlled so as to ensure mechanical maintenance during the time required for structure integrity, and at the same time ensuring that the device or material need not be manually removed, since the material undergoes resorption.
  • compositions may be used in combination with other materials, such as collagen, fibrinogen, and other natural proteins; hyaluronic acid, dextran, or other polysaccharides; or polyethylene oxide, polyhydroxyalkanoates, or other polyesters, to produce blended materials to provide a larger range of physical and biological properties, for applications, such as wound dressings or membranes for the prevention of surgical adhesions.
  • other materials such as collagen, fibrinogen, and other natural proteins
  • hyaluronic acid, dextran, or other polysaccharides such as hyaluronic acid, dextran, or other polysaccharides; or polyethylene oxide, polyhydroxyalkanoates, or other polyesters
  • polyethylene oxide, polyhydroxyalkanoates, or other polyesters such as wound dressings or membranes for the prevention of surgical adhesions.
  • the protein polymer SELP3 combined with sodium hyaluronate in equal proportions by weight, may be used to prepare a film, which compared to pure hyaluron
  • compositions may be prepared in accordance with the manner described in U.S. Patent No. 5,243,038. This procedure involves synthesizing small segments of single stranded DNA of from about 15-150 nucleotides to provide a plurality of fragments which have cohesive ends, which may be ligated together to form a segment or a plurality of segments.
  • the first dsDNA fragment is cloned to ensure the appropriate sequence, followed by the addition of successive fragments, which are in turn cloned and characterized, to ensure that the integrity of the sequence is retained.
  • the fragments are joined together to form a "monomer" which then becomes the major repeating building block of the polymer gene.
  • long single strands may be prepared, cloned and characterized, generally being of at least 100 nucleotides and up to about 300 nucleotides, where the two single strands are hybridized, cloned and characterized and may then serve as the monomer or the building block.
  • the monomers may then be multimerized, having complementary termini, particularly cohesive ends, so that the polymers will have two or more monomers present.
  • the multimers may then be cloned in an appropriate vector and characterized to determine the number of monomers and the desired size polymer selected.
  • Expression can be achieved in an expression host using transcriptional regulatory regions functional in the expression host.
  • the expression host can be prokaryotic or eukaryotic, particularly bacterial, e.g. E.
  • a signal sequence may be provided for secretion of the polymer.
  • a wide variety of signal sequences are known and have been used extensively for secreting proteins which are not normally secreted by the expression host. After completion of expression, where the protein is retained in the host, the cells are disrupted and the product extracted from the lysate. Where the product is secreted, the product may be isolated from the supernatant. In either case, various techniques for purifying the products may be employed, depending upon whether the products are soluble or insoluble in the medium. Where insoluble, impurities may be extracted from the polymer, leaving the polymer intact. Where soluble, the polymer may be purified in accordance with conventional ways, such as extraction, chromatography , or the like.
  • E. coli strain EC3 containing the respective plasmid encoding each polymer shown in Table 1 below, was prepared in accordance with the methods described in U.S. Patent No. 5,243,038. Each strain was then fermented using a fed- batch method.
  • Biomass for each polymer was harvested from the fermentation broth by centrifugation in a Sorval RC3B using a H6000A rotor at 5,000 rpm for 30 minutes at 10°C to yield a packed cell paste.
  • the cell slurry was homogenized using a Manton Gaulin cell disrupter at 7-8,000 psi with three complete passes of the liquid.
  • the cell homogenate was passed through a chilled heat exchanger to maintain the temperature at 15°C or less.
  • Pancreatic DNAse was added to the homogenate to a final concentration of 1 ⁇ g/ml and stirred at room temperature for 2 hours.
  • the homogenate was centrifuged in a Sorval RC3B centrifuge using a H6000A rotor at 5,000 rpm for 1 hour at 10°C.
  • the contents of the bags were transferred to centrifuge bottles and centrifuged in a Sorval RC3B centrifuge using a H6000A rotor at 5,000 rpm for 1 hour at 10°C.
  • the supernatant was removed to a large beaker and the pH adjusted to 8.0 by addition of 30% ammonium hydroxide. Saturated ammonium sulfate was then added to reach a final concentration of 20% for SELPO, 25% for SELP8 and 3, and 33% for SELP7.
  • the solution was stirred at room temperature for 1 hour.
  • the solution was centrifuged in a Sorval RC3B using a H6000A rotor at 5,000 rpm for 30 minutes at 10°C.
  • the pellet was resuspended in 2 liters of deionized water, placed in dialysis bags, and dialyzed against 3 changes of deionized water of lOOx volume over 48 hours.
  • the contents of the bags were shell frozen and lyophilized to dryness.
  • the centrifuged homogenate supernatant was directly precipitated with ammonium sulfate at a concentration of 25%.
  • the solution was then centrifuged in a Sorval RC3B using a H6000A rotor at 5,000 rpm for 1 hour at 10°C.
  • the pellet was resuspended in 5 liters of 4M LiBr and stirred at 4°C for 16 hours.
  • the solution was centrifuged in a Sorval RC3B centrifuge using a H6000A rotor at 5,000 rpm at 10°C for 1 hour.
  • the pH of the supernatant was adjusted to pH 3.7 by slow addition of 1M acetic acid at 4°C.
  • the solution was centrifuged in a Sorval RC3B using a H6000A rotor at 5,000 rpm at 10°C for 1 hour.
  • the supernatant pH was adjusted to 8.0 by addition of ammonium hydroxide and then dialyzed against 3 changes of lOOx volume deionized water over 48 hours.
  • the solution was removed from dialysis and centrifuged in a Sorval RC3B using a H6000A rotor at 5,000 rpm at 10°C for 1 hour. Saturated ammonium sulfate was added to the supernatant to reach 25% of saturation and stirred for 1 hour.
  • the solution was centrifuged in a Sorval RC3B using a H6000A rotor at 5,000 rpm at 10°C for 1 hour.
  • the pellet was dissolved in 4.5M LiBr, placed in dialysis bags, and dialyzed against 3 changes of lOOx volume of deionized water.
  • the contents of the bags were shell frozen and lyophilized to dryness.
  • the resin was finally equilibrated with 6M urea, 20 mM Tris pH8.0 in a beaker with gentle stirring.
  • the resin was filtered in a buchner funnel until excessive liquid was removed.
  • the cake of resin was placed in a beaker and the protein solution was added.
  • the slurry was stirred gently for 1 hour.
  • the slurry was filtered in a buchner funnel and the liquid was collected in a cleaned vacuum flask.
  • 500 grams of fresh precycled and equilibrated resin was added to a clean beaker and the filtered solution was added.. The slurry was stirred gently for 1 hour and filtered again.
  • the filtered solution was once more combined with 500 grams of freshly precycled and equilibrated resin, stirred for 1 hour, and filtered.
  • the final filtered solution was placed in 6,000 molecular weight cut-off dialysis bags which had been soaked in 0.5N NaOH for at least 24 hours.
  • the solution was dialyzed against 3 changes of lOOx volume of deionized water.
  • the dialyzed solution was removed from the bags, placed in depyrogenated lyophilization flasks and lyophilized to dryness. Employing the above procedure, the following polymers were prepared.
  • SELP4 (79,574) [(VPGVG) 12 (GAGAGS) 8 ], E12S8 1.5 42.2 (SEQ ID NO.07)
  • the first and last block domain of each polymer is split within the silk blocks such that both parts sum to a whole domain. All polymers also contain an additional head and tail sequence which constitutes approximately 6% of the total amino acids.
  • SELP6 polymers which were prepared include [ (VPGVG) 32 (GAGAGS) 8 ] (SEQ ID NO:09), referred to as SELP6.
  • SELP6 polymers which were prepared include [ (VPGVG) 32 (GAGAGS) 8 ] (SEQ ID NO:09), referred to as SELP6.
  • SELP6 polymers which were prepared include [ (VPGVG) 32 (GAGAGS) 8 ] (SEQ ID NO:09), referred to as SELP6.
  • SELP6 SELP6.
  • SELP films SELP films.
  • SELP films that were approximately 0.05 mm thickness were produced by solvent evaporation.
  • a polyethylene sheet of the same area dimensions as the protein film was roughened by hand using fine grit sand paper and a fine film of cyanoacrylate glue was spread over its surface.
  • the protein film was applied to the wet surface.
  • a teflon sheet was placed on top and bottom of the polyethylene and protein layers and stainless steel plates were placed around those. The entire assembly was pressed in a Carver laboratory press at a force of 0.8 metric tons for 18 hours at room temperature.
  • the polyethylene/protein film laminated sheet was placed on a cutting board and 1.3 cm diameter discs were punched out using a stainless steel punch and rubber mallet. The discs were placed individually in stoppered glass vials.
  • Specimens were produced from each of the polymers as well as denatured collagen protein (DCP) produced identically as described for the SELP films.
  • Bovine collagen (fibrillar form, lot number 921101) was obtained from Colla-Tec, Inc. (Plainsboro, New Jersey) . It was completely solubilized in 88% formic acid producing a clear but viscous solution. All specimens were sterilized by electron beam irradiation at 2.5 +/- 0.2 Mrads. Each disk was implanted subcutaneously in the back of rats such that the protein film was in direct contact with the muscle tissue. The specimens remained in the animals for different periods of time: one, four and seven weeks post implantation.
  • the mass of the SELP film present on each specimen was determined.
  • the amino acid contribution of the SELP protein was estimated based on the total content of the amino acids G,A,S,V and P which for the pure polymers is >95%. Other amino acids potentially contributed by extraneous protein deposited onto the specimens during residence in the body were excluded from these analyses.
  • Average SELP film mass for non-implanted specimens was determined from the same batch of specimens used for implantation.
  • Average SELP film mass for retrieved specimens was similarly calculated except that replicates having values greater than two standard deviations from the mean were discarded. Deviations in many cases were due to partial retrieval of specimens that had fragmented in the tissue after implantation and may not reflect true resorption.
  • Resorption analysis was conducted statistically by analyzing four specimen population treatment groups. These were: (1) non-implanted; (2) one week post-implantation;
  • Table 2 The results from Table 2 are the values for the mass of protein film contained on specimens after implantation. Each value is the mean of at least five specimen masses as determined by amino acid composition. Table 3 displays the same values as a percent of the initial weight prior to implantation as determined by the mean mass of six specimens of the non-implanted specimens. The results indicate that upon implantation, SELPO and DCP are substantially resorbed by one week, falling below 5% of their non-implanted masses. SELP7 is substantially resorbed by four weeks with only 5.8% remaining. SELP8 and SELP3 are resorbing by seven weeks with mean values of 18.1% and 58.2% remaining, respectively. SELP4 and SELP5 films show no evidence of resorption at seven weeks.
  • SELP7 and SELP4 films have tensile strengths of 19+/-1 and 21+/-8 MPa, respectively.
  • the compositional difference between them that causes SELP7 to resorb in four weeks and SELP4 to remain intact beyond seven weeks makes little apparent difference in their tensile properties.
  • These strengths are adequate for their use in surgical and wound healing applications.
  • the observed resorption of these polymers occurs via surface erosion. This is consistent with the mechanism of degradation of SELP proteins within the body. At physiological conditions, proteins will degrade only through the action of proteases. Because endogenous proteases are high molecular weight compounds of approximately 20 kDa or greater, their diffusion into the dense SELP films will be limited. The degradation of SELP films is, therefore, progressive from the external surfaces of the material. The subject materials therefore should undergo a slow loss of mechanical integrity while being reduced in mass.
  • SELP polymers have been fashioned into a variety of forms; dense films, porous sponges, and fibrillar mats.
  • Dense films or sheets, as described above, are semi-permeable barriers which may have utility in surgical repairs by restricting fluid or gas flow, blocking cellular migration, maintaining tissue separations, and confining and protecting implanted organs or devices.
  • Their properties will vary depending on their permeability and their thickness which may range from 0.05 mm to greater than 1 mm. For example varying their thickness will effect their mechanical strength, their resistance to abrasion, and their ultimate resorption.
  • SELP polymers have been produced as three dimensional, porous sponges to serve as implantable materials that will support cell and tissue ingrowth. Preparation of SELP5 Sponges.
  • This solution was poured 6mm deep into six standard sterilized Petri dishes (mm diameter) ; covered with standard lids; placed on a small plastic tray; and placed in a - 8°C freezer overnight. After freezing, the lids were removed from the Petri dishes; the Petri dishes were placed into a 1200 ml wide mouth lyophilization flask and lyophilized to dryness. After completion of lyophilization, the sponges were removed from their Petri dishes and placed, individually, into a 100ml wide mouth flask containing 75ml of methanol at room temperature. The head space was evacuated to less than the vapor pressure of the methanol to induce eubulation and insure compete displacement of air entrained within the sponge by the methanol.
  • the sponge, wetted with methanol was allowed to stand for 5 minutes at room temperature at room temperature, methanol was removed from the sponge by washing 6 times with LAL reagent grade water (175ml per wash) and allowing each was to stand for 5 minutes.
  • the sponges, wetted by water were returned to 35mm diameter Petri dishes, frozen at -8°C, and again lyophilized.
  • the lyophilized sponges were placed into new 35mm diameter Petri dishes, lids applied and sealed with parafilm ® , placed into a plastic instrument bag, heat sealed, and sterilized using an electron beam irradiation at 2.8 Mrads.
  • the sponges were dimensionally stable when immersed in saline or water. When engorged with saline, the sponge turned from white to grey and was somewhat translucent. The engorged sponge retained its original dimensions. Minimal swelling was observed. The geometry and edges of the wet sponge remained unchanged. The observed aqueous stability of the SELP 5 sponges is different from the properties of collagen hemostatic sponges (Helistat, Marion Laboratories, Kansas City, MO) which almost immediately collapse when exposed to liquid.
  • SELP5 sponges were cut into 2 x 2 x 0.4 cm specimens and applied to 2 x2 cm full thickness dermal wounds in pigs.
  • 2 x 2 x 0.3 cm specimens of Helistat were similarly applied to wounds. After bleeding was controlled and the wound flushed with saline, the specimens were laid into the tissue void such that they would firmly contact the wound bed. The Helistat specimens became completely or partially engorged within a few seconds to several minutes after application depending on the amount of the blood in the wound. The engorged Helistat specimens collapsed and shrunk resulting in nonuniform coverage of the wound, in some cases, exposing part of the wound beds.
  • the SELP5 sponges remained substantially white during the 5 minute observation period after application indicating that they did not immediately absorb blood.
  • One corner of one specimen turned red within a minute after application. It remained physically unchanged.
  • the SELP5 sponges adhered well to the wound bed and could not be lifted out of the wound with forceps using mild tension.
  • the SELP5 sponges did not shrink upon contact with the bloody tissue and continued to completely cover the wound during observation.
  • SELP polymers can be fabricated as non-woven fibrous meshes to produce fibrillar mats which are flexible, have good drapability, and are stable in wet environments. Fibrous meshes with similar physical properties were produced from SELP5, SELP7, and SELPF using the following procedure. 1 gram of polymer was dissolved in 88% formic acid with stirring at room temperature until homogenous. For SELP5, 5 mis of formic acid were used to dissolve the lyophilized polymer. For SELP7 and SELPF, 4 and 3 mis of formic acid were used, respectively.
  • the polymer dope was drawn into a lcc polypropylene syringe, affixed with a 75mm x 20 gauge stainless steel hypodermic needle, and mounted on a Sage Instruments syringe pump (model 341B) .
  • the pump was set to deliver approximately 0.05 to 0.07 cc/minute.
  • the tip of the needle was placed at 90° to a gas stream delivered from a stainless steel needle (25mm x 20 gauge) . A more acute angle was also used.
  • the dope delivery needle and the gas delivery needle were mounted onto a steel "L"-bracket using miniature "C"-clamps and pads of neoprene rubber such that a gap of 1 mm separated their tips.
  • the tips were displaced in the vertical direction by 0.5 mm such that the gas stream passed slightly over the flanged end of the hypodermic needle.
  • the gas stream was supplied either with compressed air or high purity (extra dry) nitrogen gas.
  • Compressed air was supplied by an oiless compressor using a diaphragm pump.
  • the air in the reservoir was a ca. 8 atm pressure and was regulated down to ca. 2-6 atm before being fed to the spray apparatus. When nitrogen was used, it was delivered at 20 psi.
  • the relative humidity was less than 47%.
  • Fine filaments were formed on and around the edges of a rectangular, 1/16 inch polypropylene mesh that was used as a target approximately 7-12 inches from needle tips. Filaments streamed off the edges of the target and when they were approximately 5 cm in length, they were collected on a circular, metal wire loop of 38 mm in diameter. Filaments were collected across the loop forming a web of suspended filaments in the center. The web was removed from the loop by compressing the web between two 35mm polystyrene discs and pressing the web through the wire frame. Fibrous meshes were built up by compressing 5-8 webs between the same discs. The meshes were stabilized by flooding them with 1 ml of either 100% methanol or 100% ethanol and allowing them to dry under ambient conditions.
  • the meshes were sterilized by electron beam irradiation at a dose of 2.5 MRads. Under microscopic observation, the meshes consisted of fine filaments which varied in diameter from 0.1 to lO ⁇ m. The meshes were stable when placed in saline for more than 24 hours.
  • the meshes were applied to 2 x 2 cm partial and full thickness dermal wounds in pigs in order to investigate their biocompatibility and their ability to incorporate within the healing tissue.
  • the meshes were removed from the polystyrene discs with forceps and applied to the wound bed. The edges of the meshes could be pulled across the tissue allowing the mesh to be spread and/or rearranged over the wound.
  • the wounds were covered and examined every two days for signs of bioincompatibility. No adverse effects were observed in wounds containing SELP fibrous meshes. After 14 days, the wounds were completely epithelialized. Histological examination of tissues from wounds to which SELPF fibrous webs had been applied showed that foreign material in the form of filaments had been incorporated into the healing tissue.
  • SELP fibrous meshes are well tolerated in healing tissue. Their presence does not interfere with normal healing. In one case, SELP filaments were clearly shown to reside within the healed tissue. SELP films, meshes, and sponges can serve as resorbable packing materials that can be used to augment the loss of soft tissue that occurs during traumatic injury or surgical disection. Their application at the time of injury can encourage infiltration, overgrowth, and eventual replacement of the materials with healthy tissue. The mass of the implanted material can provide enough stability to maintain the geometric contours of the body site at which the tissue was lost. Their presence can also mechanically reinforce the wound site such that delicate, healing tissues can form while protected from further physical injury.
  • compositions have particularly desirable properties for uses in plants.
  • rate of resorption can be varied greatly, without significant changes in tensile properties.
  • the compositions can be formed in a wide variety of devices or objects, to find extensive use for a variety of purposes and context as implants.

Abstract

La présente invention concerne des copolymères caractérisés par des proportions variables d'unités récurrentes d'élastine et de fibroïne. Il est possible de faire varier fortement le coefficient d'absorption en modifiant la longueur des segments des unités récurrentes d'élastine et de fibroïne. La résistance à la traction reste relativement constante quelle que soit la composition, mais à condition qu'elle reste dans les limites de formulation spécifiées. Les compositions de copolymères et la fibroïne recombinante sont utilisables pour la production d'une grande variété d'objets formés et de masses amorphes utilisables en implants.
PCT/US1995/002772 1994-03-11 1995-03-10 Proteines synthetiques utilisables en implants WO1995024478A1 (fr)

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JP52357195A JP3378254B2 (ja) 1994-03-11 1995-03-10 移植可能なものとしての合成タンパク質
EP95913976A EP0804595B1 (fr) 1994-03-11 1995-03-10 Proteines absorbables synthetiques utilisables en implants
DE69535895T DE69535895D1 (de) 1994-03-11 1995-03-10 Resorbierbare synthetische proteine zur verwendung in implantaten

Applications Claiming Priority (2)

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US08/212,237 1994-03-11
US08/212,237 US5606019A (en) 1987-10-29 1994-03-11 Synthetic protein as implantables

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WO1995024478A1 true WO1995024478A1 (fr) 1995-09-14

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DE (1) DE69535895D1 (fr)
WO (1) WO1995024478A1 (fr)

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EP0804595B1 (fr) 2008-12-10
CA2183644A1 (fr) 1995-09-14
EP0804595A1 (fr) 1997-11-05
DE69535895D1 (de) 2009-01-22
US20030176355A1 (en) 2003-09-18
JP3378254B2 (ja) 2003-02-17
ATE417111T1 (de) 2008-12-15
JP2001508754A (ja) 2001-07-03
US6380154B1 (en) 2002-04-30
EP0804595A4 (fr) 1997-11-05
US20020045567A1 (en) 2002-04-18
US5606019A (en) 1997-02-25

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